Intelligence is highly heritable and a major determinant of human health and well-being. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16–102) and find 148 genome-wide significant independent loci (P < 5 × 10−8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

This data descriptor outlines a shared neuroimaging dataset from the UCLA Consortium for Neuropsychiatric Phenomics, which focused on understanding the dimensional structure of memory and cognitive control (response inhibition) functions in both healthy individuals (130 subjects) and individuals with neuropsychiatric disorders including schizophrenia (50 subjects), bipolar disorder (49 subjects), and attention deficit/hyperactivity disorder (43 subjects). The dataset includes an extensive set of task-based fMRI assessments, resting fMRI, structural MRI, and high angular resolution diffusion MRI. The dataset is shared through the OpenfMRI project, and is formatted according to the Brain Imaging Data Structure (BIDS) standard.

The effect of life stress on depression is moderated by a repeat length variation in the transcriptional control region of the serotonin transporter gene, which renders carriers of the short variant vulnerable for depression. We investigated the underlying neural mechanisms of these epigenetic processes in individuals with no history of psychopathology by using multimodal magnetic resonance-based imaging (functional, perfusion, and structural), genotyping, and self-reported life stress and rumination. Based on functional MRI and perfusion data, we found support for a model by which life stress interacts with the effect of serotonin transporter genotype on amygdala and hippocampal resting activation, two regions involved in depression and stress. Life stress also differentially affected, as a function of serotonin transporter genotype, functional connectivity of the amygdala and hippocampus with a wide network of other regions, as well as gray matter structural features, and affected individuals' level of rumination. These interactions may constitute a neural mechanism for epigenetic vulnerability toward, or protection against, depression.amygdala ͉ emotion ͉ environment ͉ gene ͉ hippocampus A dverse life events can reveal profound interindividual differences, rousing resilience in some and exposing susceptibility to mood disorders, including depression, in others. Diathesis-stress models have sought to explain these individual differences in terms of genetic predispositions interacting with environmental factors (1). Behavioral genetic studies have supported these models (2), with current work focusing on molecular and neural mechanism that may underlie these associations.Dysfunction of the serotonin (5-hydroxytryptophan, 5-HT) system is implicated in mood disorders, and variation within serotonergic genes has been associated with negative emotional traits such as neuroticism and harm avoidance (3). For example, higher scores in these traits are associated with a common short variant of a repetitive sequence in the transcriptional control region of the 5-HT transporter gene (5-HTT, SERT, SLC6A4), which results in low 5-HT uptake function (4). Two metaanalyses have concluded that presence of the short variant of this repeat (5-HTT-linked polymorphic region, 5-HTTLPR) is associated with higher levels of neuroticism or harm avoidance (5, 6). Although neuroticism itself is a risk factor for depression (7), the link between 5-HTTLPR genotype and depression has been more tenuous, suggesting that 5-HTTLPR genotype does not have a consistent main effect on depression but instead may be moderated through other variables (8).Caspi et al. (9) conducted a 23-year longitudinal study in a large sample of individuals who were genotyped for the 5-HTTLPR. They found that carriers of the 5-HTTLPR short variant showed more depressive symptoms, diagnosed depression, and suicidality as a function of stressful life events than individuals homozygous for the 5-HTTLPR long variant, thus demonstrating a significant gene-by-environment (...